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Review

Cellular mechanisms underlying obesity-induced arterial stiffness

Published Online:26 Mar 2018https://doi.org/10.1152/ajpregu.00235.2016

Abstract

Obesity is an emerging pandemic driven by consumption of a diet rich in fat and highly refined carbohydrates (a Western diet) and a sedentary lifestyle in both children and adults. There is mounting evidence that arterial stiffness in obesity is an independent and strong predictor of cardiovascular disease (CVD), cognitive functional decline, and chronic kidney disease. Cardiovascular stiffness is a precursor to atherosclerosis, systolic hypertension, cardiac diastolic dysfunction, and impairment of coronary and cerebral flow. Moreover, premenopausal women lose the CVD protection normally afforded to them in the setting of obesity, insulin resistance, and diabetes, and this loss of CVD protection is inextricably linked to an increased propensity for arterial stiffness. Stiffness of endothelial and vascular smooth muscle cells, extracellular matrix remodeling, perivascular adipose tissue inflammation, and immune cell dysfunction contribute to the development of arterial stiffness in obesity. Enhanced endothelial cortical stiffness decreases endothelial generation of nitric oxide, and increased oxidative stress promotes destruction of nitric oxide. Our research over the past 5 years has underscored an important role of increased aldosterone and vascular mineralocorticoid receptor activation in driving development of cardiovascular stiffness, especially in females consuming a Western diet. In this review the cellular mechanisms of obesity-associated arterial stiffness are highlighted.

INTRODUCTION

Cardiovascular (CV) disease (CVD) is the leading cause of death not only in the United States and but also worldwide (3, 30). Arterial stiffness is an independent risk factor that contributes to the development and progression of CVD as evidenced by epidemiological studies (5, 129). The prevalence of obesity in the United States and worldwide is increasing in epidemic proportions, leading to increases in the incidence of arterial stiffness and associated CVD (87, 121, 122). The driving forces that contribute to obesity-associated arterial stiffness are increased consumption of a diet rich in saturated fat and refined carbohydrates [i.e., a Western diet (WD)] and a sedentary lifestyle (5, 23, 25, 138). Furthermore, the obesity-associated development of vascular stiffness is more common in women than men, and obese and insulin-resistant women lose the CVD protection normally afforded to them (9, 82) (Fig. 1).

Fig. 1.

Fig. 1.Causes and consequences of obesity-associated arterial stiffness. RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; M1 and M2, macrophages; IL-10, interleukin 10; Treg, regulatory T cell; Th1 and Th17, T helper 1 and 17 cells; ER, endoplasmic reticulum; eNOS, endothelial nitric oxide synthase; PAI-1, plasminogen activator inhibitor 1; TPA, tissue plasminogen activator; CVD, cardiovascular disease; CKD, chronic kidney disease.
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Arterial stiffness is associated with components of cardiorenal metabolic syndrome (CRS), a constellation of interactive cardiac and metabolic risk factors, including overweight/obesity, hypertension, insulin resistance/hyperinsulinemia, metabolic dyslipidemia, and microalbuminuria/impaired renal function (6, 103) (Fig. 1). Although arterial stiffness increases with cardiovascular aging, the process is accelerated and occurs earlier in the presence of obesity, insulin resistance, and diabetes (54, 74). Therefore, prevention and treatment directed to attenuation of arterial stiffness are emerging as important targets for improved outcomes for CVD and chronic kidney disease (CKD) in those with obesity and diabetes (9, 53). Development of arterial stiffness is a complex process that is driven by the interaction of endocrine factors and cytokines, as well as interactions between different vascular cellular components, the extracellular matrix (ECM), perivascular adipose tissue (PVAT), and immune cells in the vasculature (5, 19, 53). In this review we focus on cell-specific mechanisms that promote arterial stiffening (Fig. 2), including the role of diet-induced obesity-related abnormalities of the endothelium as a critical determinant of vascular stiffening. This review includes a discussion of the role of endothelial abnormalities in the promotion of impaired endothelial nitric oxide (NO) synthase (eNOS) activation and associated increases in vascular stiffness. We also discuss the role of vasoactive factors in promoting arterial stiffness, the emerging role of cell-specific mineralocorticoid receptor (MR) activation in promoting endothelial cortical stiffness via endothelial Na+ channel (EnNaC) activation, and the impact of a decrease in bioavailable NO. We also address the concept that a reduction of bioavailable NO leads to activation of transglutaminase 2 (TG2), a collagen cross-linking enzyme, thereby promoting vascular fibrosis. We further describe the role of maladaptive immune inflammatory responses and oxidative stress in the development of endothelial dysfunction and arterial stiffening. In addition, we briefly review the emerging role of PVAT in promoting arterial stiffening. We then address a vulnerable population, namely, obese/diabetic females, who are susceptible to diet-induced obesity-mediated arterial stiffening and associated increases in CVD and CKD.

Fig. 2.

Fig. 2.Endothelial cell (EC)-macrophage-vascular smooth muscle cell interactions in obesity-associated arterial stiffness. Impaired insulin metabolic signaling in ECs leads to decreased activation of endothelial nitric oxide (NO) synthase (eNOS) and NO bioavailability. Increase in endothelial Na+ channel (EnNaC) activity occurs due to mineralocorticoid receptor (MR)-induced activation of serum/glucocorticoid regulated kinase 1 (SGK1) and increased EnNaC expression, which result in increased influx of Na+ and polymerization of F actin, leading to endothelial cortical stiffness. This leads to impaired flow-mediated release of NO. Increased oxidative stress due to RAAS-induced activation of NADPH oxidase, xanthine oxidase, and mitochondrial oxidative stress results in increased destruction of NO. eNOS uncoupling leads to further decreases in bioavailable NO. Decreased bioavailable NO causes increased expression of adhesion molecules on ECs, favoring monocyte recruitment. Decreased bioavailable NO also results in macrophage (MΦ) activation, M1 macrophage polarization, and oxidative stress. This leads to further destruction of NO. Decreased bioavailable NO results in transglutaminase 2 (TG2) activation, which promotes collagen cross-linking and causes cortical stiffness, which impairs flow-mediated NO production. Decreased heme oxygense 1 (HO-1) activity further contributes to the decrease in bioavailable NO, thereby promoting arterial stiffness. ECM, extracellular matrix; ERK1/2, extracellular-regulated kinase 1/2; IRS-1, insulin receptor substrate-1; PI3K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; S6K1, S6 kinase 1.
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ARTERIAL STIFFNESS, CRS, AND PROGRESSION OF CVD AND CKD: CHICKEN-AND-EGG RELATIONSHIP

The relationship between arterial stiffness and the development of CRS and the progression of CVD and CKD appears to be a chicken-and-egg dilemma (7, 122). Arterial stiffness in obese children often precedes the development of hypertension, suggesting that arterial stiffness is one of the earliest biomarkers for increased CVD risk (36). Although hypertension is considered an important risk factor for the development of vascular remodeling and stiffness as an adaptive process, a cause-and-effect relationship exists between hypertension, especially systolic hypertension, and aortic stiffness (92). Arterial stiffness is often increased in overweight/obese humans and animal models before development of hypertension (35). Based on the magnitude of the increase in arterial stiffness, an incremental increase occurs in the development of hypertension (74). Moreover, rodent studies show that arterial stiffness precedes hypertension in mice fed a translational high-fat/high-fructose diet (i.e., WD) and that removal of this diet results in decreased arterial stiffness (139).

Increased arterial stiffness is significantly associated with cardiovascular and renal dysfunction, as well as CVD and CKD (20–22, 39, 54, 86). Increased systolic pressure and decreased diastolic pressure, resulting in increased pulse pressure, are caused by stiffening of the central arteries. An increase in systolic pressure increases cardiac afterload, left ventricular mass, and oxygen demand, whereas a decrease in diastolic pressure impairs coronary blood flow. These changes can result in left ventricular remodeling, ischemia, and fibrosis, all of which contribute to left ventricular diastolic dysfunction and coronary heart disease (16, 57, 83). However, development of diastolic dysfunction also occurs independent of alterations in blood pressure, perhaps driven by endothelial stiffness and dysfunction, which promote cardiomyocyte stiffness and cardiac fibrosis (8, 58). Arterial stiffness promotes kidney disease, and an increase in arterial stiffness is also considered a promoter of CVD in patients with CKD (20, 39, 137).

MEASUREMENT OF ARTERIAL STIFFNESS

Noninvasively, in vivo measurement of arterial stiffness is usually accomplished by 1) ultrasound measurement of arterial compliance and distensibility, 2) measurement of the velocity of the pressure wave traveling between two segments of an artery to determine pulse wave velocity (PWV), and 3) measurement of augmentation pressure divided by blood pressure to determine the augmentation index (108). PWV is considered an index for arterial wall stiffness, whereas the augmentation index is related to both arterial wall stiffness and wave reflections, which in turn are dependent on variations in heart rate and peripheral resistance (53). PWV measurement is considered the gold standard for evaluation of vascular stiffness (53, 80). PWV in animal models is usually determined by measurement of the pressure wave at the aortic arch and downstream in the lower abdominal aorta (26). Ex vivo measurements of arterial stiffness are often accomplished by uniaxial or biaxial loading of arterial segments and study of pressure-diameter and force-length behavior (26, 135). The use of atomic force microscopy (AFM) greatly enhances the sensitivity for determination of endothelial vascular smooth muscle cell (VSMC) and cardiomyocyte stiffness ex vivo and in vitro (58, 116). AFM, in combination with fluorescence imaging, is used to simultaneously measure vascular cell stiffness and cytoskeletal dynamics. A novel method combining AFM and confocal imaging has been used to examine cortical actin reorganization in VSMCs (114, 115).

ARTERIAL FUNCTIONAL AND STRUCTURAL ABNORMALITIES PROMOTING OBESITY-ASSOCIATED ARTERIAL STIFFNESS: ROLE OF CELLULAR AND ECM INTERACTIONS PROMOTING ARTERIAL STIFFNESS IN DIET-INDUCED OBESITY

Arterial stiffness in obesity is associated with structural and functional changes in the intimal, medial, and adventitial layers of the vasculature (119). The endothelium is a component of the arterial intima, which is separated from the media by the internal elastic lamina. The medial layer in larger conduit vessels consists of elastic lamina that are arranged as concentric layers and interspersed with smooth muscle cells and collagen (78, 123). The adventitial layer is enriched with fibroblasts, collagen, immune cells, and adipose tissue (123). Arterial stiffness is regulated by plasma-derived factors, as well as factors derived from the different layers of the vascular wall. Moreover, interactive signaling between different cells of the vascular wall modulates structure and function of cellular and noncellular components (53, 75, 110a, 149). Intimal thickening is a complex process that is associated with endothelial dysfunction and fibrotic remodeling. Although ECM remodeling due to quantitative and qualitative changes in elastin and collagen has been extensively studied, recent studies demonstrate new regulators, including matrix metalloproteinases (MMP), in modulation of the ECM (75). However, increased arterial stiffness in insulin-resistant and prediabetic states has been related to thickness of the vascular wall, suggesting that mechanisms related to vascular cells that are different from ECM remodeling are also critical in determining vascular stiffness. In addition to ECM remodeling via changes in elastin and collagen, recent studies demonstrate a role for both endothelial and vascular smooth muscle stiffness, leading to the use of such terms as “stiff endothelial cell syndrome” (68) and “smooth muscle stiffness syndrome” (115). In addition to the role of endothelial cells (ECs) and VSMCs, vascular adipose and immune cell dysfunction contribute significantly to obesity-associated arterial stiffness (19, 29, 37, 134), thereby underscoring the importance of cellular and ECM interactions in obesity-associated arterial stiffness (53, 82).

VASOACTIVE FACTORS PROMOTING OBESITY-ASSOCIATED ARTERIAL STIFFNESS

Hyperinsulinemia and Inappropriate Activation of the Renin-Angiotensin-Aldosterone System

Insulin resistance associated with hyperinsulinemia precedes the development of CVD and CKD with obesity and the CRS (14, 93, 117). This view is supported by studies demonstrating reduction of the vasorelaxation responses to insulin, but not acetylcholine, before the onset of hypertension in aged rats (112) and rats developing spontaneous hypertension (73). Systemic and CV insulin resistance and related arterial stiffness in the setting of obesity are, in large part, due to the interactions between diet and activation of the systemic, as well as tissue, renin-angiotensin-aldosterone system (RAAS) (67, 94). Increased production of angiotensin II (ANG II) and uric acid in the vasculature as a result of a high-fructose diet underscores the importance of activation of the tissue RAAS and hyperuricemia in promotion of CV remodeling and stiffness (5). ANG II and aldosterone act in concert to promote CV remodeling and stiffness in states of insulin resistance and obesity (14, 107). The critical role of activation of cell-specific vascular MRs in vascular remodeling and stiffening in states of diet-induced obesity, especially in females, is highlighted by recent studies (53, 56, 103). Patients with primary hyperaldosteronism have insulin resistance, and plasma aldosterone elevations are associated with obesity and insulin resistance in normotensive subjects (14, 56, 141). Multiple studies, including those conducted by our laboratory using different models of obesity, have shown that treatment with MR antagonists improves CV function (5, 11, 26, 66). Endothelin-1, the expression of which is increased by RAAS activation, is one of the instigators of increases in vascular stiffness and remodeling (94, 95).

Sympathetic Nervous System Activation

Obesity is often associated with increased sympathetic nervous system (SNS) activity, which is a key factor contributing to arterial stiffness and hypertension (25, 121). Hyperinsulinemia, hyperleptinemia, inappropriate activation of systemic and tissue RAAS, baroreflex dysfunction, and obstructive sleep apnea in obesity are associated with inappropriate activation of the SNS (9, 25). The precise mechanisms by which enhanced SNS activity contributes to arterial stiffness remain to be determined.

Adipocyte-Derived Factors

Metabolic changes in adipose tissue in the setting of obesity result in altered secretion of bioactive molecules and hormones, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, angiotensinogen, aldosterone-stimulating factors, aldosterone, adiponectin, dipeptidylpeptidase 4 (DPP-4), leptin, resistin, and monocyte chemoattractant protein-1 (MCP-1) (43, 99, 108). Elevated circulating levels of adipocyte-derived inflammatory cytokines may impair vascular insulin sensitivity and increase recruitment and activation of proinflammatory immune cells in the vasculature, which then contribute to development of arterial stiffness. Moreover, greater lipolytic activity in visceral adipose tissue in insulin-resistant states leads to increases in free fatty acids. Free fatty acids inhibit insulin-stimulated glucose uptake and metabolic insulin signaling in adipose, as well as vascular, tissue (25, 53). Decreased insulin metabolic signaling in ECs leads to reductions in NO production, which in turn, promote stiffening of ECs and, subsequently, vascular stiffening.

High-Fructose Diet

Increased serum uric acid levels are frequently seen in patients with obesity, insulin resistance, hypertension, CVD, and CKD (20, 55). An increase in uric acid occurs with excessive consumption of a WD that is rich in fructose (104). Indeed, fructose promotes hepatic production of uric acid (6). Our research group has reported increased cardiac xanthine oxidase activity and oxidative stress in WD-fed mice (57). Furthermore, we have observed that inhibition of tissue xanthine oxidase by allopurinol decreases vascular stiffness and prevents maladaptive immune and inflammatory responses in the vasculature (6, 27, 70). Increased expression of xanthine oxidase occurs in concert with increased RAAS activation and oxidative stress, which collectively lead to increased arterial stiffness in diet-induced obesity (20, 104).

CELLULAR MECHANSIMS OF ARTERIAL STIFFNESS

Endothelium

Decreased NO production by impaired insulin metabolic signaling and increased oxidative stress-mediated destruction of NO lead to reduced bioavailable NO.

Insulin metabolic signaling is critical for regulation of normal endothelial function and suppression of vascular stiffness (Fig. 2). In vascular ECs, insulin metabolic signaling promotes eNOS activation through an insulin receptor substrate (IRS)-1/phosphatidylinositol 3-kinase (PI3K) signaling/protein kinase B (Akt)-mediated pathway (Fig. 2) (54). On the other hand, insulin-mediated growth pathway signaling results in activation of extracellular-regulated kinase 1/2 and endothelin-1 production. Insulin metabolic signaling in ECs and VSMCs is inhibited by ANG II and aldosterone, resulting in impairment of downstream antioxidant effects and the anti-inflammatory response of the insulin metabolic signaling pathway (8). This, in turn, leads to impaired NO-mediated vasodilation responses to insulin, and decreases in NO lead to increased arterial stiffness. The mechanisms underlying RAAS-mediated insulin resistance in ECs and VSMCs are not well understood. One important signaling pathway that leads to impaired insulin metabolic signaling involves increased serine and impaired tyrosine phosphorylation of IRS-1, which is promoted by activation of kinases, including protein kinase C and p70 S6 kinase 1 (p70S6K1) (7, 8). ANG II-mediated increases in serine phosphorylation of IRS-1 through activation of the mammalian target of rapamycin/S6K1 signaling pathway result in impairment of IRS-1/2/PI3K/Akt signaling and decreased phosphorylation/activation of eNOS in ECs (65). Recently, we examined interactions between cell-specific MR activation and associated impairment of insulin metabolic signaling. Insulin metabolic signaling was compromised by impairment of Akt phosphorylation and decreased phosphorylation/activation of eNOS in WD-fed female mice. Inhibition of vascular MR activation by low-dose spironolactone or deletion of MRs in ECs prevented a decrease in eNOS phosphorylation/activation and decreases in bioavailable NO in the setting of diet-induced obesity (26, 56).

Impairment of flow-mediated vasodilation and decreased bioavailable NO: emerging role of the EnNaC in endothelial stiffness and associated inhibition of flow-mediated NO release.

Laminar blood flow-generated shear stress is an important regulator of eNOS activation and vasodilation (60). Impaired flow-mediated dilation is seen in obesity-associated arterial stiffness, which, in turn, is associated with CV insulin resistance (56). An increase in fluid shear stress normally activates IRS-1/PI3K/Akt signaling, leading to phosphorylation of eNOS. This process depends on normal structure and function of the endothelial glycocalyx and its interactions with the cytoskeleton (77, 145). Recent studies have provided new insights into the regulation of flow-mediated release of NO through interaction of the glycocalyx and the EnNaC in comparison with the epithelial Na+ channel (ENaC, in renal tubular epithelial cells) in the EC plasma membranes (34, 52). ENaC consists of three subunits, α, β, and γ: the α-subunit is essential for proper function of ENaC, while the β- and γ-subunits act as amplifiers (34). Studies on mesenteric arteries have demonstrated improvement of flow-mediated dilation in mesenteric arteries by inhibition of EnNaC activation, which is associated with increased Akt phosphorylation and eNOS activation (102).

MR activation of the EnNaC and endothelial stiffness: endothelial salt sensitivity.

Classically, activated MRs in distal renal tubular cells bind the ENaC promoter, inducing ENaC expression (52, 56). MR activation in distal renal tubular cells also mediates aldosterone-induced mammalian target of rapamycin/serum/glucocorticoid-regulated kinase 1 activation, which, in turn, causes increased accumulation of ENaC at the plasma membrane. Recent studies have demonstrated MR regulation of EnNaC. EC MR activation increases abundance of the EnNaC at the membrane, facilitating Na+ entry, triggering G-actin polymerization to F-actin. This results in stiffening of the plasma membrane and the immediate submembrane compartment and decreased caveolar release and activation of eNOS (28). We recently reported increased expression of vascular MR and EnNaC in the aorta associated with increased endothelial and arterial stiffness in WD-fed female mice. However, deletion of MR selectively in ECs resulted in decreased EnNaC activity and increased bioavailable NO, which lead to decreased arterial stiffness (56). Moreover, administration of a very low dose of the EnNaC inhibitor amiloride also improved endothelial function and reduced vascular stiffness in vivo and improved flow-mediated dilation of arteries in vitro (56, 84). These data suggest an important role for EC MRs and vascular EnNaC activation in promotion of obesity-associated arterial stiffness.

Decreased bioavailable NO is also mediated through reactive oxygen species-mediated NO inactivation.

Inactivation of NO by reactive oxygen species (ROS) is another mechanism responsible for reduced NO bioavailability in insulin-resistant states (8). In addition to sources of ROS contributed by mitochondrial activation of NADPH oxidase and xanthine oxidase, uncoupling eNOS can also generate superoxide anions (O2−) in conditions of inadequate l-arginine or tetrahydrobiopterin availability (7). Accumulating evidence suggests that angiotensin type 1 receptor and MR activation stimulates vascular NADPH oxidase activity and ROS generation. This increase in ROS, in turn, results in reduced bioavailability of NO by its conversion to peroxynitrite and by uncoupling eNOS to generate more ROS in a positive-feedback loop in ECs (65). Recently, we showed increased production of 3-nitrotyrosine, an index of oxidative stress, and reduced bioavailable NO in WD-fed female mice (26). Suppression of 3-nitrotyrosine accumulation by either MR antagonism using low-dose spironolactone (26) or deletion of MR in ECs (56) resulted in improvement of arterial stiffness. These observations further support the view that EC-mediated ROS accumulation is an important factor leading to reduced bioavailable NO. ROS production by xanthine oxidase activation in the vasculature in obesity is another mechanism leading to destruction of NO (20), and inhibition of xanthine oxidase increases bioavailable NO and decreases arterial stiffness (27). Mitochondria are also important sources of endothelial generation of ROS (53), and increased vascular ROS compromises insulin metabolic signaling and associated eNOS activation, thereby lessening bioavailable NO and promoting vascular stiffness. The increase in endoplasmic reticulum (ER) stress in obesity also contributes to generation of ROS, reductions in bioavailable NO, and increases in vascular stiffness (7).

Reduced heme oxygenase-1, reduced bioavailable NO, and arterial stiffness.

Breakdown of heme catalyzed by heme oxygenase-1 (HO-1) results in the production of carbon monoxide, biliverdin, and ferrous iron. Biliverdin is converted to bilirubin. The beneficial effects of HO-1 occur through increases in carbon monoxide and bilirubin (1, 32). HO-1 activation stimulates eNOS expression and inhibits NADPH oxidase and xanthine oxidase expression, thereby reducing ROS and enhancing NO signaling bioavailability (1, 50, 120). Induction of HO-1 reduces oxidative stress, increases bioavailable NO, and improves insulin metabolic signaling, which is associated with rodent models of obesity (1, 48).

Immune Cells

Maladaptive immune and inflammatory responses.

The role of immune and inflammatory responses in the development of arterial stiffness is increasingly recognized (3, 9, 112, 113). Inflammatory M1 macrophage activation is associated with increased production of ROS and reactive nitrogen species. Promotion of T helper 1 (Th1) responses (62) and increased expression of proinflammatory cytokines, such as TNF-α, IL-6, and MCP-1, are also associated with M1 macrophage activation. The proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, reduce vascular insulin metabolic signaling. In contrast, alternatively activated M2 macrophages, which express YM1, arginase-1, and IL-10, decrease inflammation. Increased tissue infiltration of M1 macrophages associated with accumulation of ROS and development of insulin resistance is also enhanced by Th1 cells and cytotoxic CD8+ T cells. On the other hand, inflammatory T cells are suppressed by T lymphocyte regulatory (Treg) cells (63). Treg cell accumulation is decreased in adipose tissue from mice fed a high-fat diet (9). Treg cells normally improve insulin sensitivity, in part by inhibition of M1 macrophage polarization, as well as M2 macrophage-mediated secretion of IL-10. This process corrects impaired insulin metabolic signaling caused by proinflammatory cytokines and inhibits NADPH oxidase and reduces ROS generation in ECs (63). IL-17 is a cytokine secreted by T helper 17 (Th17) cells. Th17 cells are elevated in obese and type 2 diabetes mellitus patients as well as obese mice (9, 63). Increased IL-17 levels are associated with decreased insulin sensitivity and insulin resistance, whereas suppression of IL-17 levels results in increased insulin sensitivity (148). These immune mechanisms that contribute to impaired insulin metabolic signaling are also associated with immune inflammatory responses that promote arterial stiffness (25, 42, 112, 140).

EC-immune cell interactions in macrophage recruitment and activation.

Recruitment of immune cells to vascular and adipose tissue occurs early during the development of vascular dysfunction and arterial stiffness (9). Immune cell recruitment is a sequential, multistep event resulting from interaction of monocytes and EC adhesion molecules (105, 111) (Fig. 2). Endothelial inflammation and oxidative stress appear to be critical in the recruitment of immune cells, including monocytes and macrophages, to ECs (51, 53). The significance of EC-dependent macrophage recruitment is underscored by significant inhibition of macrophage recruitment to the heart in EC MR knockout (KO) mice (58, 146). In this regard, EC MR activation leads to increased expression of adhesion molecules, as well as expression of MCP-1, which promotes attraction and adhesion of monocytes to ECs (15, 58). Both decreased availability of NO and increased accumulation of ROS increase the expression of EC adhesion molecules and MCP-1 (79). Decreased bioavailable NO also stimulates the M1 macrophage proinflammatory response once the macrophages have infiltrated the vasculature (71).

Inflammasomes.

Inflammasome activation also contributes to promotion of the inflammatory response, insulin resistance, type 2 diabetes, and vascular stiffness through increases in IL-1β (46). Exposure to pathogens or activation of danger-associated signals in inflammatory states results in inflammasome activation (106). In obesity, vascular inflammasomes are activated by elevated tissue levels of palmitate and ceramide (46, 106). Uric acid also activates inflammasomes, and the improvement seen after allopurinol administration may, in part, be caused by suppression of this proinflammatory response (20, 104).

Vascular Smooth Muscle Cells

Recent studies demonstrate that intrinsic VSMC alterations also contribute to arterial stiffness (115). VSMC stiffness increases in response to vasoactive agonists associated with adhesion to ECM proteins (47, 115). Recent studies favor the role of VSMC MRs in vascular stiffness. Deletion of MRs, specifically in VSMCs, decreases accumulation of ROS in the vasculature and is associated with decreased vasoconstriction in response to agonists (88). In addition, deletion of smooth muscle cell MRs prevents an aldosterone/salt-induced increase in arterial stiffness (40). However, the mechanisms regulating the passive stiffness of VSMCs and increased adhesive properties of VSMCs to ECM are not clearly known, and further studies will define the role of MRs in VSMC regulation of arterial stiffness in the setting of obesity.

Extracellular Matrix

Collagen accumulation and cross-linking of collagen.

ECM remodeling and fibrosis are important contributors to arterial stiffness (53). The ECM is composed of collagen, elastin, and specialized proteins, such as fibronectin and proteoglycans. Extracellular remodeling includes changes in accumulation of ECM material as well as qualitative changes in the ECM. Accumulation of vascular collagen is seen in obesity-associated arterial stiffness. One of the underlying mechanisms for this process is enhanced transforming growth factor-β/SMAD signaling and increased connective tissue growth factor expression (26, 53). We recently showed that vascular MR expression and activation are enhanced with increased aortic fibrosis in female WD-fed mice (26, 56). In addition to collagen accumulation, increased cross-linking is mediated by increased activation of TG2 and/or lysyl oxidase or by nonenzymatic glycation of collagen by advanced glycation end products (AGEs). In mice fed a high-fat–high-refined carbohydrate WD, arterial stiffness is associated with altered collagen structure, such as cross-linking of collagen by TG2 activation (132). TG2 catalyzes formation of ε (γ-glutamyl) lysine isopeptide, in a Ca2+-dependent manner (132). The substrates for TG2 include collagen, fibronectin, laminin, and actin (139). Endothelial glycocalyx polymerization involves increased accumulation of F actin, which, in turn, contributes to increased endothelial cortical stiffness and associated reductions in eNOS activation and reduced bioavailable NO (38, 39). Decreased bioavailable NO, in turn, promotes TG2 activation (33). Transforming growth factor-β has also been shown to increase TG2 expression and activation (132). Activation of TG2 is regulated by the presence of Ca2+ as well as nitrosylation (61). Nitrosylation promoted by NO decreases TG2 activity and inhibits release of TG2 from ECs (61). Therefore, a decrease in bioavailable NO, as seen in obesity, may significantly contribute to cross-linking of collagen by causing activation and extracellular release of TG2 (61). In this regard, increased TG2 activity and cross-linking of collagen with increased arterial stiffness have been demonstrated in mice fed a high-fat–high-refined carbohydrate diet (139). Cross-linking of collagen by lysyl oxidase also contributes to arterial stiffness in obesity (135). In addition to cross-linking of collagen, lysyl oxidase-derived hydrogen peroxide has also been shown to contribute to arterial stiffening through the p38 mitogen-activated protein kinase signaling pathway (85). Increased lysyl oxidase also causes abnormal elastin structure, which contributes to arterial stiffness (85).

Accumulation of AGEs due to consumption of a diet high in fructose increases collagen cross-linking, thereby promoting arterial stiffness (64, 97, 124). AGEs are formed by nonenzymatic glycation of proteins, lipids, and nucleic acids formed via a Maillard reaction. AGE accumulation occurs with aging, but the process is accelerated in obesity (124). However, AGE-induced effects on arterial stiffness are mediated by multiple mechanisms, including decreases in bioavailable NO and activation of the receptor for AGEs (10, 124). Obesity-mediated activation of the receptor for AGEs occurs by multiple mechanisms, including inappropriate activation of the RAAS and dysregulation of the DPP-4/incretin system (10, 143, 144).

Elastin breakdown.

Vascular elastin breakdown is also an important cause of arterial stiffness. Several MMPs and their endogenous inhibitors of metalloproteinases are implicated in the breakdown of elastin (49, 125). Among MMPs, MMP-2, MMP-9, and MMP-12 play an important role in ECM remodeling in the vasculature and arterial stiffness (12, 13, 26, 75). Serum levels of MMP-9 are increased in obese patients, and MMP-2 levels were increased in obese adults and children (42). Adiponectin has been shown to decrease MMP-2 activity, and increased MMP-2 activity in hypertensive obese children is associated with decreased adiponectin production (13). MMPs are secreted by ECs, VSMCs, macrophages, and T lymphocytes (49). In addition to their effects on elastin degradation, MMPs also induce proinflammatory responses that promote arterial stiffness (49, 91). We recently reported increased breakdown and distortion of elastic lamina in the aorta of female mice fed a WD. This same breakdown was attenuated in WD-fed EC MR KO mice, suggesting a role for EC-specific MR activation in modulating elastin breakdown (56).

Perivascular Adipose Tissue

Adipose tissue was originally considered a simple lipid rich in connective tissue, but the presence of immune cells, production of biologically active compounds, and specialized functions of adipocytes suggest the role of an endocrine tissue for adipose tissue. Recent studies demonstrated dynamic interconversion of brown and white adipose tissue with altered cytokine production and remodeling responses. This underscores the importance of adipose tissue as one of the therapeutic targets to reduce CVD (17, 44, 59, 96, 101). In this regard, adipose tissue surrounding the vasculature, PVAT, not only serves as a structural support for most arteries but also secretes molecules with paracrine effects on the vasculature (41, 127). PVAT secretory products include proinflammatory/anti-inflammatory molecules and vasoconstrictive/vascular relaxing factors, including TNF-α, IL-6, angiotensinogen, aldosterone-stimulating factors, aldosterone, adiponectin, DPP-4, leptin, resistin, and MCP-1 (43, 99, 108). Hyperplasia of PVAT and infiltration of proinflammatory immune cells in PVAT have been demonstrated in obesity and insulin resistance (25). Maladaptive responses of PVAT also contribute to low-grade vascular inflammation and impaired endothelial function and vascular stiffness (33, 127). PVAT loses its normal vascular protective effects in obesity and insulin resistance (53). Enhanced infiltration of inflammatory immune cells in PVAT is associated with endothelial dysfunction (44). Dysfunctional PVAT adjacent to the vessel wall promotes vascular stiffness through secretion of several vasoactive factors, including aldosterone. In this regard, all components of the RAAS, including ANG II and angiotensin-(1–7) and their receptors, are expressed in PVAT. Treatment with an angiotensin receptor antagonist significantly lowered adipose tissue weight and improved PVAT-mediated vascular relaxation (72). Moreover, administration of the MR antagonist spironolactone also prevented endothelial NO uncoupling caused by β-adrenergic stimulation in a PVAT-dependent manner (133). Increased levels of IL-6 in PVAT are seen in obesity, and aortic PVAT-derived IL-6 contributes to arterial stiffness in LDL receptor-deficient mice (29). Decreased levels of adiponectin in PVAT also contribute to impaired vascular relaxation and promotion of vascular stiffness (53, 69, 134). Recent studies have demonstrated an important role for PVAT-produced adiponectin in attenuating vascular oxidase stress and vascular stiffness (2). Diet-induced obesity is also associated with increased arginase activity, which leads to l-arginine deficiency in PVAT and uncoupling of eNOS, thereby resulting in reduced bioavailable NO (142). Decreased bioavailable NO causes activation of TG2 and arterial stiffness (5). In addition to adipokines and NO, an unidentified adipocyte-derived relaxing factor appears to play an important role in the regulation of vascular tone by PVAT. The adipocyte-derived relaxing factors released by PVAT cause vasorelaxation, which occurs by promoting the opening of voltage-dependent K+ channels in the plasma membrane of smooth muscle cells (43, 76). The vascular relaxing properties of PVAT are abrogated in obesity. Indeed, PVAT from obese rats with metabolic syndrome was observed to promote impaired mesenteric vascular relaxation mediated via prostaglandins (89). Aortic PVAT from diet-induced obese mice potentiates vascular contractility through cyclooxygenase-derived adipose tissue-derived contracting factor (90). Furthermore, PVAT from obese swine augmented KCl-induced coronary contractions (100). These obese animal PVAT-mediated abnormal vascular responses were abolished in the presence of inhibitors of Ca2+ channels. Obese PVAT also inhibits ATP-sensitive K+ channel-mediated dilation in lean and obese coronary vessels (98). Together, these studies support the idea that maladaptive adipose tissue remodeling has a critical role in reducing vascular relaxation and promoting arterial stiffness in obesity.

SEX DIFFERENCES IN CV STIFFNESS

There is emerging evidence in obese and diabetic females that development of systemic and tissue insulin resistance is a strong risk factor for CV stiffness and CVD (24, 31, 110). Females lose the CVD protection normally afforded to them when they are obese, insulin-resistant, and diabetic (26, 81). Obese women have substantially increased vascular stiffness compared with age-matched men. The mechanisms for the abrogation of CV protection in premenopausal obese and diabetic women likely involve a number of mechanisms (109). Cross talk between MRs and estrogen receptors (ERs) may promote expression and activation of vascular ENaC. Indeed, binding of 27-hydroxycholesterol to ERα is one mechanism that may contribute to deleterious effects on arterial stiffness in females with obesity and insulin resistance (82, 130, 131, 147). We have developed a translationally relevant model of WD-induced CV stiffness and diastolic dysfunction, studied insulin resistance in WD-fed females, and demonstrated abrogation of the female advantage in the setting of obesity. We have further explored the role of elevated aldosterone levels and MR activation in CV dysfunction and vascular stiffness in WD-fed females. In contrast to studies where females are protected in a high-fat-diet model, females fed a high-saturated-fat–high-refined-carbohydrate WD exhibit systemic and CV tissue insulin resistance and cardiac and vascular stiffness. We observed that a WD has an earlier adverse impact on CV tissue insulin metabolic signaling in females than males (81), and this impaired insulin signaling was associated with increased CV stiffness (26). Elevated plasma aldosterone levels were accompanied by increased CV MR expression in WD-fed female mice (26, 56). MR antagonism with very low-dose spironolactone administration prevented this diet-induced CV stiffness in females (26). Furthermore, endothelial-specific deletion of MRs prevented WD-induced aortic stiffness in concert with decreased expression of ENaC and increased bioavailable NO (56). Recently, we demonstrated an improvement in arterial stiffness in WD-fed EC ERα KO mice, suggesting that ERα signaling contributes to this arterial stiffness (82).

AGING

Two-thirds of American adults are overweight or obese (121). Obesity contributes to CVD in all age groups, including those >50 yr of age (126, 128). Arterial stiffening drives an increase in systolic pressure compared with diastolic pressure with increasing age (45). Although arterial stiffening with aging is usually attributed to increases in collagen deposition, reductions in and breaking of elastin also contribute to this process. Furthermore, increased cross-linking of connective tissue promoted by TG2 and AGEs is also important in promoting this aging process (61, 118). Enhanced oxidative stress and inflammation are seen in both age- and obesity-associated arterial stiffening (136). Enhanced PVAT generation of ROS has been reported in aging as well, thereby raising the possibility of PVAT-derived ROS as a potential mediator of arterial stiffness and the inflammatory response in aging processes accelerated with obesity (18, 134).

CONCLUSIONS

Arterial stiffness in obesity is emerging as an independent risk factor promoting the progression of CVD and CKD. Interactions of excess caloric intake with inappropriately activated RAAS and inflammation promote vascular insulin resistance, decreased bioavailable NO, maladaptive immune inflammatory response, and dysfunctional PVAT, all of which promote cardiac and vascular stiffness. High dietary fructose-induced production of uric acid and enhanced tissue xanthine oxidase activity amplify vascular inflammation and promote arterial stiffness. ECM remodeling and connective tissue cross-linking contribute to arterial stiffness in obesity. Recent studies highlight the role of cell-specific MR activation in the development of arterial stiffness in diet-induced obesity. Recent investigation in our laboratory also implies that increased signaling through the endothelial MR in association with WD consumption may also paradoxically increase EnNaC activation, thereby promoting vascular stiffness. The mechanisms revealed by these studies may help drive preventive and therapeutic strategies directed at CV stiffness that will reduce the inordinate CVD risk in overweight persons.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grants HL-073101 and HL-107910 (to J. R. Stanton) and Department of Veterans Affairs Biomedical Laboratory Research and Development Grant 0018 (to J. R. Stanton).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.R.A. and G.J. prepared figures; A.R.A., G.J., and J.R.S. drafted manuscript; A.R.A., G.J., and J.R.S. edited and revised manuscript; A.R.A., G.J., and J.R.S. approved final version of manuscript.

ACKNOWLEDGMENTS

The authors thank Brenda Hunter for editorial assistance and Brady Barron for supervising the research conducted in our laboratory.

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AUTHOR NOTES

  • Address for reprint requests and other correspondence: James R. Sowers, University of Missouri, D109 Diabetes Center HSC, One Hospital Dr., Columbia, MO 65212 (e-mail: ).
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